Background:
A functional anesthetic target has long been suspected to reside within mitochondria, and disruption of bioenergetic capacity is believed to play a role in the anesthetic response. Unfortunately, the exact mechanism by which changes in mitochondrial target activity result in clinically relevant anesthetic endpoints remains unknown. Here, the authors leveraged knowledge of propofol toxicity to guide drug discovery and uncover a previously unknown pharmacologic target within mitochondria. They hypothesized that, like propofol, quinone analogs would interfere with electron transfer, cause excessive proton leak within mitochondria, and induce hypnosis. The authors tested their hypothesis using the short-chain coenzyme Q analog ubiquinone-5 (Ub5) and aimed to characterize its anesthetic phenotype in the mouse and elucidate the source of Ub5-induced mitochondrial leak.
Methods:
Anesthetic phenotype was assessed in vivo in the mouse using behavioral and neurophysiological approaches. The authors measured biologic activity in isolated mitochondria using polarography and spectrophotometry and identified source of proton leak using pharmacologic inhibitors, mutant mouse strains, and transport activity assays in proteoliposomes. Finally, they assessed cardiotoxic effects in the isolated-perfused mouse heart ex vivo.
Results:
Coenzyme Q analogs caused uncompensated proton leak in developing cardiomyocyte mitochondria and reversible cardiotoxicity in a manner reminiscent of propofol. Tail vein injection of Ub5 induced short-lived loss of righting, electroencephalogram changes consistent with a deep state of anesthesia, and reversible decreases in neuronal calcium transients and mitochondrial membrane potential in vivo. Precipitous decline in mitochondrial membrane potential played a role in Ub5-induced unconsciousness, and the authors identified the aspartate-glutamate carrier Aralar as a functional target and source of Ub5-mediated proton leak.
Conclusions:
The data indicate that uncompensated mitochondrial proton leak is an important mechanistic contributor to the anesthetic response in addition to electron transport inhibition. These findings advance the authors’ understanding of how anesthetics induce hypnosis and lay the foundation for next-generation drug discovery.